1. Technical Field
The invention relates to macrocyclic pyrimidine compounds, compositions comprising the compounds, methods for making the compounds, and methods of treating conditions and disorders using such compounds and compositions.
2. Description of Related Technology
Histamine modulates a number of physiological activities, acting through specific histamine receptors (reviewed in Parsons and Ganellin, British Journal of Pharmacology (2006) 147, S127-S135; Igaz and Hegyesi, in Histamine: Biology and Medical Aspects (2004), 89-96; Editor(s): A. Falus; Published S. Karger AG, Basel). Four histamine receptors have been identified as playing distinct physiological roles. These are the histamine H1 receptor, the histamine H2 receptor, the histamine H3 receptor, and the histamine H4 receptor. Compounds that modulate, or affect, the activity of these receptors may be used to treat diseases. For example, the well-known role of H1 receptors in modulating allergic reaction has led to the clinical development of drugs that treat allergic rhinitis and other diseases by antagonizing the action of naturally-occurring, or endogenous, histamine in the body. Histamine H2 receptor antagonists have been developed and proven clinically useful in treating diseases associated with excess stomach acidity. The histamine H3 receptor is found predominantly on nerve terminals in the central nervous system (CNS) and the peripheral nervous system, i.e., periphery, and antagonists of this receptor have been documented in studies that benefit mammalian cognitive processes, improve wakefulness, suppress symptoms of allergic rhinitis, and suppress weight gain. The histamine H4 receptor is the most recently identified histamine receptor and has been characterized as a distinct histamine receptor. The histamine H4 receptor has been found in a number of mammalian tissues and has been determined to modulate a number of physiological processes, including immunological function.
By use of histamine H4 ligands in animal disease models as well as in in vitro and ex vivo studies, the histamine H4 receptor has been demonstrated to play an important role in various physiological and pathophysiological processes. Separately, in experiments with histamine H4 deficient (knock out) animals and cells and tissues from such histamine H4 deficient animals, the histamine H4 receptor has been demonstrated to play an important role in various physiological and pathophysiological processes. Examples of diseases and disorders where histamine H4 receptors have been found to play an important role include, for example, asthma, allergy, rheumatoid arthritis, and inflammation.
The activity of histamine H4 receptors can be modified or regulated by the administration of histamine H4 receptor ligands. The ligands can demonstrate antagonist, inverse agonist, or partial agonist activity.
Histamine H4 ligands in different structural classes have been reviewed (Schwartz, Expert Opinion in Therapeutic Patents (2003) vol. 13, pp. 851-865). It would be beneficial to provide additional compounds demonstrating H4 receptor-modulating activity that can be incorporated into pharmaceutical compositions useful for therapeutic methods.